ABSTRACT ? Project 2 (Leader: Dr. Genevieve Fouda, Duke University) More than 1.8 million children world-wide live with HIV, and every year more than 150,000 new pediatric HIV infections occur. Current standard of care commits HIV-infected children to lifelong, daily antiretroviral treatment (ART). However, ART does not cure HIV due to the persistence of virus reservoirs that re-establish infection following treatment interruption. Therapeutic interventions that lower the size of the virus reservoir could delay virus rebound when ART is interrupted. Such reservoir reduction can be achieved by very early ART initiation, but this is not practical for the roughly half of pediatric HIV cases stemming from postnatal infection via breast milk HIV transmission because their diagnosis is delayed. Thus, postnatally infected children would benefit greatly from development of adjunct therapies, including immune-based strategies. Indeed, studies have indicated that antibody passive immunization and therapeutic vaccination can impact virus reservoirs, but their relevance and effect in the maturating infant immune system remains unknown. A first step toward development of immunotherapeutic interventions for postnatally infected infants thus will require identifying the immune mechanisms associated with virus control after breast milk transmission. Thus the objective of this Project is to identify immune correlates of virus rebound in the setting of breast milk transmission. Our central hypothesis is that enhancement of specific antiviral immune responses in ART- treated, simian-human immunodeficiency virus (SHIV)-infected infant rhesus macaques (RMs), either through antibody passive immunization or through vaccination, will reduce the virus reservoir and delay virus rebound after treatment interruption. We propose the following aims: 1) Assess kinetics of virus-specific immune responses in ART treated SHIV-infected infant RMs; 2) Define the impact of adjunct therapy with polyclonal polyfunctional antiviral antibodies on virus rebound in an infant RM model of breast milk transmission and ART; and 3) Evaluate the impact of enhancing T cell responses through vaccination on virus rebound in SHIV- infected ART-treated infant RMs. This Project will interact with the proposed Program's other Project and utilize the services of the Administrative and Statistical Core, the Nonhuman Primate Core, and Virology Core. This Project will identify immune correlates associated with reservoir clearance and/or delay in virus rebound in a highly relevant animal model of postnatal transmission and thereby guide design of pediatric-specific immune- based interventions towards an HIV functional cure.